EBioMedicine 2 (2015) 1494–1499

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EBioMedicine

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Research Article

Distribution of Health Effects and Cost-effectiveness of Varicella

Vaccination are Shaped by the Impact on Herpes Zoster
Alies van Lier a,⁎, Anna Lugnér a, Wim Opstelten b, Petra Jochemsen a, Jacco Wallinga a, François Schellevis c,d,
Elisabeth Sanders a,e, Hester de Melker a, Michiel van Boven a
a
Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven, The Netherlands
b
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands
c
NIVEL, Netherlands Institute for Health Services Research, PO Box 1568, 3500 BN Utrecht, The Netherlands
d
Department of General Practice & Elderly Care Medicine/EMGO Institute for Health and Care Research, VU University Medical Center, v/d Boechorststraat 7, 1081 BT Amsterdam,
The Netherlands
e
Department of Paediatric Immunology and Infectious Diseases, Wilhelmina's Children Hospital, University Medical Center Utrecht, PO Box 85090, 3508 AB Utrecht, The Netherlands

a r t i c l e i n f o a b s t r a c t

Article history: Introduction: Varicella zoster virus (VZV) is the etiological agent of varicella and herpes zoster (HZ). It has been
Received 31 July 2015 hypothesised that immune boosting of latently infected persons by contact with varicella reduces the probability
Received in revised form 7 August 2015 of HZ. If true, universal varicella vaccination may increase HZ incidence due to reduced VZV circulation. To inform
Accepted 7 August 2015 decision-making, we conduct cost-effectiveness analyses of varicella vaccination, including effects on HZ.
Available online 8 August 2015
Methods: Effects of varicella vaccination are simulated with a dynamic transmission model, parameterised with
Dutch VZV seroprevalence and HZ incidence data, and linked to an economic model. We consider vaccination
Keywords:
Varicella zoster virus
scenarios that differ by whether or not they include immune boosting, and reactivation of vaccine virus.
Vaccination Results: Varicella incidence decreases after introduction of vaccination, while HZ incidence may increase or
Transmission model decrease depending on whether or not immune boosting is present. Without immune boosting, vaccination is
Cost-effectiveness expected to be cost-effective or even cost-saving. With immune boosting, vaccination at 95% coverage is not
expected to be cost-effective, and may even cause net health losses.
Conclusions: Cost-effectiveness of varicella vaccination depends strongly on the impact on HZ and the economic
time horizon. Our findings reveal ethical dilemmas as varicella vaccination may result in unequal distribution of
health effects between generations.
© 2015 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction
Universal vaccination against acute communicable diseases such as
smallpox, poliomyelitis, diphtheria, and measles have been very suc-
cessful by reducing circulation of the pathogens and associated burden
of disease (Ehreth, 2003). A live attenuated vaccine against varicella
was developed in the early 1970s, and licensed for universal use in
healthy children in the late 1980s and early 1990s. Since then, varicella
vaccination has been introduced in an increasing number of countries
(Bonanni et al., 2009; European Centre for Disease Prevention and
Control (ECDC), 2014). Over the years, the varicella vaccine has proved
⁎ Corresponding author at: RIVM-National Institute for Public Health the Environment,
Centre for Infectious Disease Control, Department of Epidemiology and Surveillance, PO
Box 1, 3720 BA Bilthoven, The Netherlands.
E-mail addresses: alies.van.lier@rivm.nl (A. van Lier), anna.lugner@rivm.nl (A. Lugnér),
wopstel2@umcutrecht.nl (W. Opstelten), petra.jochemsen@rivm.nl (P. Jochemsen),
jacco.wallinga@rivm.nl (J. Wallinga), f.schellevis@nivel.nl (F. Schellevis),
lieke.sanders@rivm.nl (E. Sanders), hester.de.melker@rivm.nl (H. de Melker),
michiel.van.boven@rivm.nl (M. van Boven).
effective in preventing varicella zoster virus (VZV) infection and varicella
disease in clinical trials and after introduction in national immunisation
programmes (NIP) (Varicella and Herpes Zoster Vaccines, 2014). Conse-
quently, recommendations for varicella vaccination have been issued by
the World Health Organization, the Centers for Disease Control and
Prevention, and the European Centre for Disease Prevention and Control
(Varicella and Herpes Zoster Vaccines, 2014; Marin et al., 2007; European
Centre for Disease Prevention and Control (ECDC), 2015).
Even though the varicella vaccine is safe and effective, not all
developed countries have included vaccination in their NIPs (Bonanni
et al., 2009). This is mainly due to the low perceived severity of varicella
compared to other vaccine-preventable diseases, and uncertainties
about the effect of varicella vaccination on the epidemiology of diseases
caused by VZV. VZV is the etiological agent of both varicella after primary
infection, and of herpes zoster (HZ) after reactivation of the virus. Hope-
Simpson hypothesised that HZ incidence increases when circulation of
VZV in the population decreases (Hope-Simpson, 1965). This so-called
exogenous boosting hypothesis is based on the supposition that lack of
exogenous immune boosting in latently infected persons might increase

http://dx.doi.org/10.1016/j.ebiom.2015.08.017
2352-3964/© 2015 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 A. van Lier et al. / EBioMedicine 2 (2015) 1494–1499
their risk of HZ. The hypothesis is shored by several findings, e.g., the
lower incidence of HZ in adults with children than in adults without
children (Brisson et al., 2002), and the negative association between
HZ incidence and increasing exposure to varicella, social contacts with
children or occupational contacts with ill children (Thomas et al., 2002).
There are, however, also studies that do not support this hypothesis and
the issue is therefore not definitively settled (Ogunjimi et al., 2013).
Cost-effectiveness of varicella vaccination might be affected by sever-
al interacting factors. First, reducing VZV circulation by varicella vaccina-
tion might result in an increase in HZ incidence (Schuette and Hethcote,
1999; Brisson et al., 2000; Gidding et al., 2005; Karhunen et al., 2010)
and an age-shift for HZ to younger ages, resulting in productivity loss.
HZ in elderly is more severe than varicella in children, with patients
often suffering from severe, long-lasting neurological pain (Oxman,
2000). Second, varicella vaccination will shift the average age at primary
infection in unvaccinated individuals to higher ages, as is well-known
from epidemiological theory and observations (Anderson and May,
1991). Since varicella is more severe in older than younger persons
(Heininger and Seward, 2006), and infection during pregnancy can result
in congenital varicella syndrome (Enders and Miller, 2000), these effects
also need to be factored in. Third, with populations ageing in many devel-
oping countries, a (transient) increase in HZ cases is expected, which may
impact on cost-effectiveness analyses. Fourth, the varicella vaccine con-
tains a live attenuated virus, which itself can cause reactivation. However,
there is limited quantitative evidence on the frequency of HZ among var-
icella vaccinees, especially on the long term (Heininger and Seward,
2006). Most cost-effectiveness analyses did not include such effects of
varicella vaccination on HZ (Rozenbaum et al., 2008) and may therefore
give too optimistic results.
With the aim to inform decision-making regarding introducing
varicella vaccination, we provide a comprehensive cost-effectiveness
analysis that includes the above factors. The Dutch situation is used as
an example because of the good quality data reflecting the pre-
vaccination situation in developed countries with a temperate climate
in which varicella is in general a childhood disease. Because of the ex-
pected age-shift for both varicella and HZ, we pay special attention to
generational differences by studying the incidence of both syndromes
by birth cohort.
2. Methods
2.1. Data Overview
The analyses are primarily based on two large datasets. First, in-
formation on infection status is contained in a population-based
serological study of 6251 samples carried out in the Netherlands in
2006–2007 (van Lier et al., 2013). Second, information on age-
specific HZ incidence rates is retrieved from 7026 HZ cases reported
to general practitioners in 2002–2011 (Stirbu-Wagner et al., 2011).
In addition, we have made use of national demographic data of Sta-
tistics Netherlands and information on Dutch contact patterns
(Mossong et al., 2008). Details are given in the Supplement.
2.2. Model Structure, Statistical Analysis, and Vaccination Scenarios
We investigate the effectiveness of universal childhood varicella vac-
cination using an age-structured transmission model (Guzzetta et al.,
2013). First, we use data on varicella and HZ incidence to estimate all
relevant transmission parameters in the pre-vaccination era. In a second
step, we use the transmission model armed with quantitative parame-
ter estimates to anticipate the impact of varicella vaccination on the
age-specific incidences of varicella and HZ. We consider a two-dose var-
icella vaccination programme with a first dose at 12 months and a sec-
ond dose at 4 years of age, as this would nicely fit in the existing NIP
(Supplement). We simulate a vaccination programme starting (arbi-
trarily) on January 1, 2020, and analyse four vaccination scenarios,
1495
labelled A–D (Table 1). The scenarios differ by whether or not they
include immune boosting (scenarios A and C with effect of boosting; B
and D without effect of boosting), and whether or not reactivation of
vaccine virus is included (scenarios A–B no vaccine virus reactivation;
C–D with reactivation). For each scenario, we consider four vaccination
coverages: 0%, 25%, 50%, and 95%. Throughout, we assume a vaccine
effectiveness of 90% after one dose of varicella vaccine and 95% after
two doses, which is reasonable in view of the evidence summarised by
WHO (Varicella and Herpes Zoster Vaccines, 2014). We assume that
after one vaccine dose there is small probability of breakthrough varicella
(10% per infectious contact) that is less infectious (50%) than primary
varicella, and we assume that there is no breakthrough varicella after
two vaccine doses in persons who respond to vaccination. For simplicity,
we do not consider potential waning of vaccine effectiveness. Demo-
graphic data of the Netherlands are applied to the modelled incidences
of varicella and HZ to obtain the estimated number of cases by year, and
by birth cohort. Details on the estimation procedures, model assumptions,
and vaccination scenarios are given in the Supplement.
2.3. Cost-Effectiveness
We use the output of the transmission modelling with vaccination as
input for the cost-effectiveness analyses. All assumptions and parame-
ters regarding treatment costs, vaccination costs, production losses,
and QALY (quality-adjusted life-year) losses are described in Data Sup-
plement 3. Because age-shifts play an important role in the analyses,
and clinical severity of varicella differs by age, we distinguish health
care use and QALY loss of varicella in patients aged b 15 versus ≥ 15
years, following Van Hoek et al. (van Hoek et al., 2012). Similarly,
QALY loss of HZ is also age-dependent (van Hoek et al., 2012).
To determine cost-effectiveness of varicella vaccination, taking into
account both varicella and HZ, the incremental cost-effectiveness ratio
(ICER) is calculated, i.e., the difference in cost between a vaccination
programme and no vaccination, divided by the difference in QALYs be-
tween a vaccination programme and no vaccination. In accordance with
Dutch guidelines for pharmacoeconomic research, costs (4%) and QALYs
(1.5%) are discounted from 2020 onwards (Hakkaart-van Roijen et al.,
2011). We take a societal costs perspective that includes productivity
loss. Costs are expressed in euros (€), at the 2012 price level.
First, the summation from 2020 onwards of the discounted net costs
(= costs minus savings), are calculated separately for each year. The
discounted net QALYs (= QALYs gained minus QALYs lost) are
Table 1
Overview of the four main vaccination scenarios implemented in the dynamic transmis-
sion model based on different assumptions about the effects of immune boosting on her-
pes zoster and vaccine VZV reactivation, and with various vaccination coverages.
Vaccination scenariosa
Assumptions A B C D
Boosting b
Yes No Yes No
Vaccine VZV reactivationc No No Yes Yes
Vaccination coverage (%)d 0;25;50;95 0;25;50;95 0;25;50;95 0;25;50;95
a
General assumptions for all scenarios:
- Two-dose varicella vaccination programme (first dose: 12 months, second dose: 4
years of age), starting on January 1, 2020;
- Vaccine effectiveness of 90% after one dose, 95% after two doses;
- Probability breakthrough varicella after one dose: 10% per infectious contact (relative
infectiousness after one dose 50%), no breakthrough varicella after two doses.
b
Yes = exogenous immune boosting has an effect on the probability of VZV reactiva-
tion, No = no effects of immune boosting.
c
Yes = vaccine VZV is able to reactivate with the same rate as wild type VZV, No = no
reactivation of vaccine VZV.
d
0%: baseline without varicella vaccination, 25%: conservative coverage because of
expected limited acceptance of varicella vaccination due to the perceived low severity of
varicella, 50%: intermediate coverage, 95%: highest coverage based on regular Dutch vac-
cination coverage data.
1496 A. van Lier et al. / EBioMedicine 2 (2015) 1494–1499
calculated in the same way. Subsequently, the ICER is calculated as the
discounted net costs divided by the discounted net QALYs cumulatively,
to get the costs per QALY up to that specific year. The ICER is calculated
only when the net QALYs is positive, i.e., when there is health gain. We
use a variable time horizon, i.e., we calculate the ICER each year over a
total period of 180 years, instead of choosing one single time point as
cut-off. Vaccination is considered cost-effective below an ICER threshold
of €20,000 per QALY, a limit often used in the Netherlands (Houweling
et al., 2010).
2.4. Sensitivity Analyses
In the univariate sensitivity analyses we consider i) a vaccination
scenario with two doses given around the age of 1 year, ii) a cost-
effectiveness analysis that does not include HZ related costs and
QALYs, iii) a cost-effectiveness analysis without discounting of costs
and QALYs, iv) a cost-effectiveness analysis with both costs and QALYs
discounted at the same rate (4%), v) a cost-effectiveness analysis with
a 50% reduced vaccine price, and vi) analyses with alternative cost-
effectiveness thresholds (€50,000–€200,000 per QALY).
3. Results
3.1. Effects of Vaccination
We fit the transmission model to the age-specific VZV serological
and HZ incidence data, and obtain quantitative estimates for all epide-
miological parameters in the absence of vaccination (Supplement).
The results of the two best-fitting model scenarios (with and without
immune boosting) are shown with the data in Fig. 1.
The impact of vaccination on the incidence of varicella and HZ is
shown in Fig. 2 by birth cohort. The four scenarios (Table 1) yield iden-
tical results for varicella, and differ substantially for HZ. Specifically, in
scenario B, both varicella and HZ incidence decrease with increasing
vaccination coverage in vaccinated cohorts, and the incidence of varicel-
la and HZ in unvaccinated cohorts is marginally affected. In contrast, in
scenario A, the incidence of HZ increases in comparison with scenario B
in the vaccinated cohorts, and also in unvaccinated cohorts. This is due
to the reduced immune boosting in latently infected persons, which
has profound impact especially when vaccination coverage is high.
Namely, in scenario A, with high (95%) vaccination coverage the lifetime
risk of HZ approaches 100% in unvaccinated persons who are born in the
vaccination era, and reaches 80% in cohorts born just before introduc-
tion of vaccination (i.e., 2010–2020). In scenario C the situation is
even more extreme, as here even all vaccinated cohorts have a high life-
time risk of HZ if vaccination coverage is high. In the scenarios that
Fig. 1. VZV seroprevalence in 2006–2007 (blue dots) and herpes zoster incidence in the
period 2002–2011 (orange dots) in the Netherlands. The sizes of the dots reflect sample
sizes. Total numbers of sera and herpes zoster cases are 6251 and 7026, respectively.
Thin grey lines indicate fits of transmission models with and without immune boosting.
See the Supplement for details.
include boosting (scenarios A and C), the effect of vaccination on vari-
cella and HZ is much smaller in case of low to intermediate vaccination
coverage (25% or 50%).
The full impact of vaccination on reducing the incidence of varicella
is observed within 5–10 years into the vaccination programme (Fig. 3).
In contrast, the potential increase in HZ incidence occurs on a much lon-
ger timescale of 20–60 years after start of vaccination (Fig. 3). In the
long term, the incidence of HZ decreases to low values in scenarios A
and B. In contrast, in scenario C the long-term incidence of HZ increases
with increasing vaccination coverage. In scenario D, the HZ incidence is
stable.
At high vaccination coverage (95%), there is a significant increase in
the age at varicella from 4 to almost 15 years of age in all scenarios, and
even to 24 years of age for some birth cohorts (Figures S7–S8). In sce-
narios A and B there is a strong transient increase over time in the
mean age at HZ to persons in their seventies. In the long run, the
mean age at HZ decreases by almost 10 years to persons in their fifties
in scenarios with immune boosting (scenarios A and C) (Figure S7–S8).
3.2. Cost-Effectiveness of Vaccination
Fig. 4 shows a stylised overview of the cost-effectiveness analyses at
high vaccination coverage (95%). Full results are presented in
Figures S10–S11. Models without immune boosting (scenarios B and
D) are characterised by health gains and limited costs or even savings,
while models with immune boosting (scenarios A and C) are
characterised by health losses and high costs. In models without im-
mune boosting (scenarios B and D), vaccination at high coverage is ex-
pected to be cost-effective (scenario D) or even cost-saving (scenario
B). In contrast, in models with boosting (scenarios A and C), vaccination
at high coverage is either not cost-effective within 180 years (scenario
C) or cost-effective only on the very long term (N130 years; scenario
A), with exception of the first ten years after start of vaccination when
varicella incidence is low and HZ incidence not yet increased. In these
scenarios, disadvantages for unvaccinated birth cohorts (i.e., QALY loss
due to increased HZ) out-weigh health benefits for vaccinated cohorts.
If vaccination coverage is reduced to 50% or 25% (Figure S12–S13),
the effect of vaccination on both net costs and net QALYs are smaller.
As a result, scenario B ceases to be cost-saving (but remains cost-
effective).
3.3. Sensitivity Analyses
The sensitivity analyses (see Supplement) show that the epidemio-
logical impact of vaccination is similar when two vaccine doses are
administered around the age of 1 year (Figure S9). If costs and QALYs
for HZ are ignored, varicella vaccination is expected to be cost-
effective after 5 years of vaccination (Figure S14). Without discounting,
scenario A is cost-effective 30 years earlier than in the main analyses,
scenario B is cost-saving 10 years earlier, scenario C remains not cost-
effective, and scenario D is cost-effective 10 years earlier (Figure S15).
When costs and QALYs are discounted at the same rate (4%), scenario
A is not cost-effective anymore on the long run, illustrating that the
cost-effectiveness hinges on unequal discounting rates in the main anal-
yses (Figure S16). Finally, if the vaccine price is halved, scenario A is
cost-effective slightly earlier, scenario B is cost-saving 20 years earlier,
scenario C remains not cost-effective, and scenario D is cost-effective
10 years earlier, and even becomes cost-saving (Figure S17).
Summarising, in all analyses the ICER decreases strongly in the first
years after start of vaccination when upfront costs of the vaccination
programme are offset by strong health gains due to reduced VZV circu-
lation. In scenarios with immune boosting (scenario A and C), there is a
similarly strong increase in the ICER after approximately 20 years when
health benefits caused by reduced VZV circulation are nullified by even
stronger negative health effects caused by increasing HZ incidence.
Because of abrupt changes in the ICER, using a higher threshold for
 A. van Lier et al. / EBioMedicine 2 (2015) 1494–1499
Fig. 2. Impact of varicella vaccination by birth cohort on the occurrence of varicella and herpes zoster. The vaccination programme started in 2020. See Table 1 for an overview of scenarios.
cost-effectiveness (e.g., €200,000 per QALY) has relatively small impact
on the conclusions regarding cost-effectiveness of vaccination.
4. Discussion
Our analyses show that health effects and cost-effectiveness of vari-
cella vaccination depend crucially on the impact on HZ, and the time
horizon for economic analysis. In the absence of exogenous immune
boosting, vaccination with high coverage is expected to be cost-
effective and may even be cost saving, while it is not expected to be
cost-effective on reasonable time scales (b100 years, say) if immune
boosting is present. In our analyses, the worst case would be a scenario
with immune boosting and reactivation of vaccine virus. In such a sce-
nario, benefits of reduced varicella incidence are offset by a strong in-
crease in HZ incidence. In all our analyses varicella vaccination would
be cost-effective on a short time-scale of less than 20 years, when poten-
tial negative effects on HZ incidence are not yet felt. Altogether, we con-
clude that the decision on whether varicella vaccination is cost-effective
or not, is dominated by the epidemiological impact of vaccination, and
hardly affected by the choices regarding the height of the threshold
for cost-effectiveness.
Results by birth cohort further reveal that varicella vaccination may
result in inequalities of health effects between generations. Specifically,
in scenarios with immune boosting the benefits of vaccination accrue in
vaccinated birth cohorts, while the burden and costs are largely due to
HZ in unvaccinated persons. Especially cohorts born just before the in-
troduction of vaccination are expected to pay the price for the health
gain in vaccinated cohorts. This is true not only in terms of the propor-
tion affected by HZ but also in terms of cost-effectiveness as the age at
reactivation is expected to shift to working ages. In addition, in
1497
unvaccinated persons the age at infection with VZV increases to older
children and young adults, resulting in more severe varicella and poten-
tially an increase in congenital and perinatal varicella. These results re-
veal an ethical dilemma for policy makers, as groups not included in the
vaccination programme may be exposed to a substantially increased
health hazard.
Incorporating a catch-up campaign of varicella vaccination does not
prevent the health inequalities mentioned above. Although the addi-
tional disease burden due to HZ can be partly mitigated by HZ vaccina-
tion among older adults (van Hoek et al., 2012), it is debatable whether
it would be logical to make additional costs for HZ vaccination to make
varicella vaccination, which is possibly not cost-effective on its own,
cost-effective.
Earlier studies have shown potential consequences of varicella vacci-
nation on HZ incidence (Schuette and Hethcote, 1999; Brisson et al.,
2000; Gidding et al., 2005; Karhunen et al., 2010). However, only a lim-
ited number of studies on the cost-effectiveness of varicella vaccination
(Rozenbaum et al., 2008; van Hoek et al., 2012; Thiry et al., 2003; Unim
et al., 2013; Bilcke et al., 2013) incorporated the potential effects of var-
icella vaccination on herpes zoster incidence. According to the reviews
and additional studies mentioned above, universal childhood varicella
vaccination is expected to be cost-effective or even cost-saving from a
societal perspective (or cost-effective under the health payer perspec-
tive), when effects on herpes zoster are ignored. However, if potential
effects on herpes zoster are incorporated, as suggested by the immune
boosting hypothesis of Hope-Simpson, vaccination is either not cost-
effective or cost-effective on a very long time scale of several decades.
Our analyses have revealed profound trans-generational differences in
the distribution of health benefits and losses, thereby underscoring
the importance to study effects beyond the mean in the population at
1498 A. van Lier et al. / EBioMedicine 2 (2015) 1494–1499
Fig. 3. Impact of varicella vaccination over time on the occurrence of varicella and herpes zoster. The vaccination programme started in 2020. See Table 1 for an overview of scenarios.
large. Second, exploration of different scenarios regarding occurrence of
immune boosting and reactivation of vaccine virus give justice to the bi-
ological uncertainties. Third, ICERs are calculated using a variable time
horizon, and our analyses have shown that the time horizon for eco-
nomic assessment is crucial when health benefits and losses accrue on
different time scales.
We acknowledge some study limitations. First, even though differ-
ent studies seem to be tipping toward the immune boosting hypothesis,
there are also negative reports and the issue remains not yet definitely
settled (Ogunjimi et al., 2013). In our study we have considered a
broad range of biologically plausible scenarios, inevitable leading to a
Fig. 4. Stylised overview of the cost-effectiveness of high-coverage (95%) varicella vaccina-
tion programme over time. Incremental cost-effectiveness ratio (ICER) threshold is set
at €20,000 per QALY. This figure is based on data contained in Figures S10–S11. See the
Supplement for details and sensitivity analyses.
broad range of potential outcomes. Second, due to lack of data on break-
through infection after two vaccine doses and on possible waning of im-
munity, the model could not be parameterised including these possible
vaccine imperfections. Third, we assume that reactivation of vaccine
virus occurs at the same rate as for circulating virus. In practice, reacti-
vation after vaccination is expected to be rarer than after natural infec-
tion but the magnitude of this difference remains largely unknown. As a
consequence, our scenarios with reactivation of vaccine virus probably
represent a worst case scenario with regard to HZ increase after vaccina-
tion. Finally, due to lack of information no costs or effects have been
included for long-term effects of congenital varicella syndrome.
5. Conclusions
We conclude that cost-effectiveness of varicella vaccination is
strongly affected by its impact on HZ, and the time horizon for economic
assessment. Although there are reports of increasing HZ incidence in
populations with varicella vaccination (Goldman and King, 2013; Kelly
et al., 2014), the time since the introduction of vaccination has probably
been too short to draw definitive conclusions. Furthermore, evidence on
vaccine VZV reactivation on the long-term is still limited (Heininger and
Seward, 2006). Therefore, optimal decision-making on varicella vacci-
nation would involve judicious and repeated weighing of the various
scenarios as more evidence comes in from countries with vaccination
programmes already in place.
 A. van Lier et al. / EBioMedicine 2 (2015) 1494–1499
Funding
This study was supported by the National Institute for Public Health
and the Environment (RIVM), no additional funding has been acquired.
Competing Interests
All authors have completed the ICMJE uniform disclosure form at
www.icmje.org/coi_disclosure.pdf and declare no support from any
organisation for the submitted work; no financial relationships with
any organisations that might have an interest in the submitted work
in the previous three years; and no other relationships or activities
that could appear to have influenced the submitted work.
Dr. Sanders reports receiving grant support from pharmaceutical
companies GlaxoSmithKline and Pfizer, and fees paid to the institution
(University Medical Center Utrecht) for membership of independent
data monitoring board from GSK and Pfizer, outside the submitted
work.
Authors' Contributions
HdM and JW initiated this study. MvB designed the transmission
model and performed statistical analyses, and AL/AvL designed the
cost-effectiveness analyses with input on scenario and parameter
choices from HdM, JW, WO, and PJ. AvL, AL, and MvB analysed the
data and drafted the manuscript. HdM, JW, WO, PJ, FS, and ES
interpreted the analyses and revised the manuscript. All authors read
and approved the final manuscript.
Acknowledgements
We would like to thank Albert Jan van Hoek (Public Health England)
for providing the original QALY loss data for herpes zoster by age,
Willem Luytjes and Nynke Rots (RIVM) for their input on scenario and
parameter choices, Odo Diekmann (Utrecht University) for helpful dis-
cussions, and Loes Soetens (RIVM) for her ideas on graphical presenta-
tion of the results.
Appendix A. Supplementary Data
Supplementary data to this article can be found online at http://dx.
doi.org/10.1016/j.ebiom.2015.08.017.
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